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Differential impact of a dyskeratosis congenita mutation in TPP1 on mouse hematopoiesis and germline

Telomerase extends chromosome ends in somatic and germline stem cells to ensure continued proliferation. Mutations in genes critical for telomerase function result in telomeropathies such as dyskeratosis congenita, frequently resulting in spontaneous bone marrow failure. A dyskeratosis congenita mut...

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Detalles Bibliográficos
Autores principales: Graniel, Jacqueline V, Bisht, Kamlesh, Friedman, Ann, White, James, Perkey, Eric, Vanderbeck, Ashley, Moroz, Alina, Carrington, Léolène J, Brandstadter, Joshua D, Allen, Frederick, Shami, Adrienne Niederriter, Thomas, Peedikayil, Crayton, Aniela, Manzor, Mariel, Mychalowych, Anna, Chase, Jennifer, Hammoud, Saher S, Keegan, Catherine E, Maillard, Ivan, Nandakumar, Jayakrishnan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Life Science Alliance LLC 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548261/
https://www.ncbi.nlm.nih.gov/pubmed/34645668
http://dx.doi.org/10.26508/lsa.202101208
Descripción
Sumario:Telomerase extends chromosome ends in somatic and germline stem cells to ensure continued proliferation. Mutations in genes critical for telomerase function result in telomeropathies such as dyskeratosis congenita, frequently resulting in spontaneous bone marrow failure. A dyskeratosis congenita mutation in TPP1 (K170∆) that specifically compromises telomerase recruitment to telomeres is a valuable tool to evaluate telomerase-dependent telomere length maintenance in mice. We used CRISPR-Cas9 to generate a mouse knocked in for the equivalent of the TPP1 K170∆ mutation (TPP1 K82∆) and investigated both its hematopoietic and germline compartments in unprecedented detail. TPP1 K82∆ caused progressive telomere erosion with increasing generation number but did not induce steady-state hematopoietic defects. Strikingly, K82∆ caused mouse infertility, consistent with gross morphological defects in the testis and sperm, the appearance of dysfunctional seminiferous tubules, and a decrease in germ cells. Intriguingly, both TPP1 K82∆ mice and previously characterized telomerase knockout mice show no spontaneous bone marrow failure but rather succumb to infertility at steady-state. We speculate that telomere length maintenance contributes differently to the evolutionary fitness of humans and mice.